We measured the plasma concentrations of the natural anticoagulant protein C and its cofactor protein S in 17 patients with severe proteinuria. In addition, prothrombin and antithrombin III levels were measured in the same group of patients. These results were compared with results obtained in 26 healthy controls and a group of 14 patients with chronic renal insufficiency (CRI) but minimal proteinuria. Protein C, protein S, and prothrombin levels were not significantly different between healthy controls and patients with CRI. However, protein C, protein S, and prothrombin levels were significantly elevated in 71%, 82%, and 76%, respectively, of patients with proteinuria. Antithrombin III levels were decreased in three of these 17 patients with proteinuria. Plasma concentrations of protein C, protein S, and prothrombin correlated significantly with each other and were inversely correlated with serum albumin concentrations. In three patients, high protein C, protein S, and prothrombin levels returned to normal during remission of the proteinuric state. Proteins C and S were not detectable in the urine of two patients with high-grade proteinuria. Thus, the plasma levels of the vitamin K-dependent, natural anticoagulant protein C and its cofactor protein S are increased in patients with proteinuria. The elevated plasma levels of other vitamin K-dependent proteins, such as prothrombin, suggest a generalized elevation in vitamin K-dependent protein synthesis in patients with proteinuria.